Water soluble prodrugs of azole compounds

ABSTRACT

Water-soluble prodrugs of triazole antifungal compounds having a secondary or tertiary hydroxy group are provided. More particularly, new water-soluble triazole antifungal compounds are provided having the general formula                    
     wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxyl group and n, R 1  and R 2  are as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of co-pending application Ser. No.09/315,606 filed May 20, 1999 which claims priority of U.S. ProvisionalApplication No. 60/103,560 filed Oct. 7, 1998 and U.S. ProvisionalApplication No. 60/086,435 filed May 22, 1998.

BACKGROUND OF THE INVENTION

This invention relates to a new class of azole derivatives, methods fortheir use, and processes for their production. The compounds describedherein are useful for the treatment of fungal infections in humans andother mammals. The present invention provides a compound represented bythe general formula

wherein A is the non-hydroxy portion of a triazole antifungal compoundof the type containing a secondary or tertiary hydroxy group, n is 0 or1, and R¹ and R² are hydrogen, C₁-C₆ alkyl or C₂-C₆ alkenyl, said alkylor alkenyl group being optionally substituted by a hydroxy ordimethylamino group, or R¹ and R² taken together with the nitrogen towhich they are attached forms a heterocyclic group of the formula

where R⁷ is hydrogen, CHO, COR¹³ or C₁-C₆ alkyl in which the alkyl groupmay be optionally interupted by an oxygen atom or NR¹⁴ and may besubstituted by hydroxy, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each independentlyhydrogen, hydroxy, CONH₂, or C₁-C₆ alkyl, said alkyl group beingoptionally substituted by hydroxy, R¹³ is C₁-C₆ alkyl and R¹⁴ ishydrogen or C₁-C₆ alkyl; or a pharmaceutically acceptable salt thereof.

DESCRIPTION OF THE PRIOR ART

Triazole antifungal compounds are well known in the prior art. Of theseveral classes known, one particularly potent class contains a tertiaryhydroxyl group. For example, U.S. Pat. No. 5,648,372 discloses that(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-olhas anti-fungal activity.

The utility of this class of compounds is limited by their low watersolubility. One method of addressing this problem was disclosed inEuropean Patent Application 829478, where the water solubility of anazole antifungal agent was increased by attaching a linked amino-acid tothe azole portion of the molecule.

Alternatively, WO 97/28169 discloses that a phosphate moiety can beattached directly to the tertiary hydroxyl portion of the anti-fungalcompound, e.g. the compound having the formula

Examples describing the use of N-N-dialkylaminomethyl benzoatederivatives as prodrugs can be found in H. Bundgaard et al, J. Med.Chem. 32, 2503 (1989); E. Jensen et. al. Int. J. Pharmaceut. 58, 143(1990); and H. Bundgaard, Drugs of the Future 16, 443 (1991).

SUMMARY OF THE INVENTION

It has now been found that triazole anti-fungal compounds containing asecondary or tertiary hydroxyl group, including(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol,may be converted into prodrugs with superior properties to thosepreviously disclosed by attaching an amino-containing moiety via alinking group. Specifically, the invention covers compounds of theformula:

wherein A is the non-hydroxy portion of a triazole antifungal compoundof the type containing a secondary or tertiary hydroxy group, n is 0 or1, and R¹ and R² are hydrogen, C₁-C₆ alkyl or C₂-C₆ alkenyl, said alkylor alkenyl group being optionally substituted by a hydroxy ordimethylamino group, or R¹ and R² taken together with the nitrogen towhich they are attached forms a heterocyclic group of the formula

where R⁷ is hydrogen, CHO, COR¹³ or C₁-C₆ alkyl in which the alkyl chainmay be optionally interupted by either an oxygen atom or NR¹⁴ and may besubstituted by a hydroxy group, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are eachindependently hydrogen, hydroxy, CONH₂ or C₁-C₆ alkyl, said R⁸, R⁹, R¹⁰,R¹¹ or R¹² alkyl group being optionally substituted by hydroxy, R¹³ isC₁-C₆ alkyl and R¹⁴ is hydrogen or C₁-C₆ alkyl; or a pharmaceuticallyacceptable salt thereof.

In a preferred embodiment, A represents the non-hydroxy portion of atriazole antifungal compound of the type containing a tertiary hydroxygroup.

The various methylamine substituents of formula I may be attached ineither an ortho, meta, or para relationship to the ester substituent,with the preferred attachment being either meta or para.

In a preferred embodiment A can be

wherein R³ represents phenyl substituted by one or more (preferably 1-3)halogen atoms;

R⁴ represents H or CH₃;

R⁵ represents H, or taken together with R⁴ may represent ═CH₂;

R⁶ represents a 5- or 6 membered nitrogen containing ring which may beoptionally substituted by one or more groups selected from halogen, ═O,phenyl substituted by one or more groups selected from CN,(C₆H₄)—OCH₂CF₂CHF₂ and CH═CH—(C₆H₄)—OCH₂CF₂CHF₂, or phenyl substitutedby one or more groups selected from halogen and methylpyrazolyl.

Nitrogen containing heterocycles which R⁶ may represent includetriazolyl, pyrimidinyl, and thiazolyl.

Specific examples of A include, but are not limited to, the following:

In addition to the application of the present invention to structurescontaining a tertiary alcohol, it should also be understood that thisdiscovery can be applied to anti-fungal agents which contain secondaryalcohols. Some examples include, but are not limited to, the following:

Representative R¹, R² and n values are shown below:

(where A represents the non-hydroxy portion of a triazole anti-fungalcompound of the type containing a tertiary or secondary hydroxyl group)

R

DEFINITIONS

The term “pharmaceutically acceptable salt” as used herein is intendedto include the non-toxic acid addition salts with inorganic or organicacids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric,maleic, acetic, citric, succinic, benzoic, fumaric, mandelic,p-toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic,trifluoroacetic, hydroiodic, hydrobromic, and the like.

The term “halogen” includes chloro, bromo, fluoro and iodo, and ispreferably chloro or fluoro, and most preferably fluoro.

The aliphatic “alkyl” and “alkenyl” groups may be straight or branchedchains having the specified number of carbon atoms, e.g. in the case ofC₁-C₆ alkyl, the alkyl group may have from 1 to 6 carbon atoms.

DETAILED DESCRIPTION

Preferred embodiments of the present invention, including in each casepharmaceutically acceptable salts thereof are:

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N-diethylaminomethyl)benzoyloxy]methoxy]butane(compound of example 1)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N-di-(2-hydroxyethyl)aminomethyl)benzoyloxy]methoxy]butane (compound of example 2)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(4-methyl-piperazinyl)methyl]benzoyloxy]methoxy]butane(compound of example 3)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N-dimethylaminomethyl)benzoyloxy]methoxy]butane(compound of example 4)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N-methyl-N-(2-hydroxyethyl)aminomethyl)benzoyloxy]methoxy]butane (compound of example 5)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N-ethyl-N-butyl)aminomethyl]benzoyloxy]methoxy]butane(compound of example 6)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(4-(2-hydroxyethyl)-1-piperazinylmethyl)benzoyloxy]methoxy]butane (compound of example 7)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(3RS-hydroxy)-1-piperidinylmethyl]benzoyloxy]methoxy]butane(compound of example 8)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4-(2RS-hydroxyethyl)-1-piperidinylmethyl]benzoyloxy]methoxy]butane(compound of example 9)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4-formyl)-1-piperazinylmethyl]benzoyloxy]methoxy]butane(compound of example 10)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4RS-hydroxy)-1-piperidinylmethyl]benzoyloxy]methoxy]butane(compound of example 11)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4-ethyl)-1-piperazinylmethyl]benzoyloxy]methoxy]butane(compound of example 12)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4RS-methyl)-1-piperidinylmethyl]benzoyloxy]methoxy]butane(compound of example 13)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[4RS-(N-piperadinyl)-1-piperidinylmethyl]benzoyloxy]methoxy]butane(compound of example 14)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N,N-dipropyl)aminomethyl]benzoyloxy]methoxy]butane(compound of example 15)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(3RS-hydroxy)-1-pyrrolidinylmethyl]benzoyloxy]methoxy]butane(compound of example 16)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N,N-diallyl)aminomethyl]benzoyloxy]methoxy]butane(compound of example 17)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(2S,6R-dimethyl-1-piperidinyl)methyl]benzoyloxy]methoxy]butane(compound of example 18)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N-ethyl-N-(2-dimethylaminoethyl)aminomethyl]benzoyloxy]methoxy]butane (compound of example 19)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(3-thiazolidinyl)methyl]benzoyloxy]methoxy]butane(compound of example 20)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N-methyl-N-(3-dimethylaminopropyl)aminomethyl]benzoyloxy]methoxy]butane (compound of example 21)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(3RS-methyl-1-piperidinyl)methyl]benzoyloxy]methoxy]butane(compound of example 22)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N-methyl-N-(2-dimethylaminoethyl)aminomethyl]benzoyloxy]methoxy]butane (compound of example 23)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N,N-bis-(2RS-hydroxypropyl)aminomethyl]benzoyloxy]methoxy]butane(compound of example 24).

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(1-piperidinyl)methyl]benzoyloxy]methoxy]butane(compound of example 25)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4-morpholinyl)methyl]benzoyloxy]methoxy]butane(compound of example 26)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-[(4-morpholinyl)methyl]benzoyloxy]methoxy]butane(compound of example 27)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-(N,N-diethylaminomethyl)benzoyloxy]methoxy]butane(compound of example 28)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-[N,N-bis(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]butane(compound of example 29)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-[(4-methyl-1-piperazinyl)methyl]benzoyloxy]methoxy]butane(compound of example 30)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[(4-morpholinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 31)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 32)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-morpholinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 33)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 34)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[(4-methyl-1-piperazinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 35)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 36)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-methyl-1-piperazinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 37)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 38)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2′-hydroxyethoxy)ethyl-1-piperazinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 39)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N-methyl-N-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 40)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-hydroxy-4-piperidinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 41)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-carbamyl-4-piperidinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 42)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2-hydroxyethyl)-1-piperazinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 43)

The more preferred embodiments of the present invention, including ineach case pharmaceutically acceptable salts thereof are:

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(4-morpholinyl)methyl]benzoyloxy]methoxy]butane(compound of example 26)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 32)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-morpholinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 33)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 34)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 36)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 38)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2′-hydroxyethoxy)ethyl-1-piperazinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 39)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N-methyl-N-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 40)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-hydroxy-4-piperidinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 41)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-carbamyl-4-piperidinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 42)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2-hydroxyethyl)-1-piperazinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 43).

The aforementioned preferred embodiments of the present invention arelisted in the table below along with their observed molecular ions (M⁺or MH⁺).

III

Mass Example R Spec  1

MH+ = 657  2

MH+ = 689  3

MH+ = 684  4

MH+ = 629  5

MH+ = 659  6

MH+ = 685  7

MH+ = 714  8

MH+ = 685  9

MH+ = 713 10

MH+ = 698 11

MH+ = 685 12

MH+ = 698 13

MH+ = 683 14

MH+ = 752 15

MH+ = 685 16

MH+ = 671 17

MH+ = 681 18

MH+ = 697 19

MH+ = 700 20

MH+ = 673 21

MH+ = 686 22

MH+ = 683 23

MH+ = 686 24

MH+ = 717 25

MH+ = 669 26

MH+ = 670 27

M+ = 670 28

MH+ = 657 29

MH+ = 689 30

MH+ = 684 31

MH+ = 716 32

MH+ = 702 33

M+ = 715 34

MH+ = 734 35

MH+ = 728 36

MH+ = 734 37

MH+ = 728 38

MH+ = 702 39

MH+ = 802 40

MH+ = 704 41

MH+ = 730 42

MH+ = 757 43

MH+ = 758

The compounds of the present invention can be made by conventionalmethods. Two suitable procedures are summarized by the followingreaction schemes. In both methods, A represents the non-hydroxy portionof a triazole anti-fungal compound of the type containing a tertiary orsecondary hydroxyl group.

X=Cl, Br or I, preferably Cl

To elaborate on Method 1, the anti-fungal parent compound of interest isconverted into ester 2 by reaction with chloride 1 in the presence of asuitable base, such as potassium hydride. The reaction can be carriedout in THF or other appropriate solvent and the product is usuallypurified by column chromatography. Chloride 1 can be prepared by thegeneral method of Iyer et al., Syn. Comm. 25, 2739, 1995 (see Method 1below in the Illustrative Examples section) or by Method 2 shown belowin the Examples). Ester 2 can be subsequently transformed intoarylmethylamine 3 by reaction with the desired dialkyl amine in DMF. Thereaction occurs between 25° C. and 100° C. and the resulting product canbe purified by recrystallization or column chromatography. If an aminesalt is used, it will be understood that one molar equivalent of anappropriate base should be added to facilitate the reaction.

The intermediates 2 of the formula

wherein the halomethyl substituent is in the ortho, meta or paraposition, preferably the meta or para position, X is chloro, bromo oriodo, preferably chloro, and A represents the non-hydroxyl portion of atriazole antifungal compound of the type containing a tertiary orsecondary hydroxyl group are another aspect of the present invention.The preferred intermediates are those having the specific “A” groupsmentioned above.

The intermediates 2 may be prepared by reacting a suitable halomethylbenzoic acid ester of the formula

wherein the halomethyl substituent of the phenyl ring is in the ortho,meta or para position, preferably the meta or para position, X is Cl, Bror I, and A represents the non-hydroxyl portion of a triazole antifungalcompound of the type containing a tertiary or secondary hydroxyl groupwith an antifungal agent A—OH wherein A is as defined above in an inertorganic solvent such as tetrahydrofuran and in the presence of base suchas potassium hydride.

To elaborate on Method 2, the anti-fungal parent compound of interest istransformed into chloromethylformate 4 by reaction with commerciallyavailable chloromethylchloroformate (Aldrich Chemical Company) in thepresence of an appropriate base in THF or other solvent at 0° C. to 50°C. Appropriate bases include potassium hydride and sodium hydride, amongothers, with the preferred base being potassium hydride. The product canbe purified by column chromatography. Chloromethylformate 4 is convertedto iodide 5 by reaction at elevated temperature with NaI in acetone. Thecrude product from this reaction can be used in the next step, or theproduct can be purified via column chromatography. In another aspectthen, the present invention provides intermediates 4 of the formula

wherein X¹ is Cl, Br or I and A is the non-hydroxy portion of a triazoleantifungal compound of the type containing a tertiary or secondaryhydroxyl group. The preferred intermediates of formula 4 are thosehaving the specific “A” groups mentioned above. Intermediates 4 may beprepared by reacting chloromethylchloroformate with an antifungal agentA—OH in which A is as defined above in an inert organic solvent such astetrahydrofuran in the presence of base and, if desired, converting theso-produced chloromethylformate of formula 4 to the correspondingcompound of formula 4 wherein X¹ is Br or I by reaction with an alkalimetal bromide or iodide. Iodide 5 is converted to the final product 7 byreaction with carboxylate salt 6 in acetonitrile or other appropriateorganic solvent. The efficiency of the reaction can be increased byadding small amounts of 18-crown-6 or other appropriate crown ether.Carboxylate salt 6 can be prepared by the method disclosed in Lombardinoet al in U.S. Pat. No. 4,623,486. The product can be purified byrecrystallization or column chromatography. If an amine salt is used, itwill be understood that one molar equivalent of an appropriate baseshould be added to facilitate the reaction. It is also possible todirectly convert chloride 4 to the final product by reaction withcarboxylate salt 6 at elevated temperatures.

It will be understood that where the substituent groups used in theabove reactions contain certain reaction-sensitive functional groupssuch as amino or carboxylate groups which might result in undesirableside-reactions, such groups may be protected by conventional protectinggroups known to those skilled in the art. Suitable protecting groups andmethods for their removal are illustrated, for example, in ProtectiveGroups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons,1991). It is intended that such “protected” intermediates andend-products are included within the scope of the present disclosure andclaims.

The desired end-product of formula I may be recovered in the form of apharmaceutically acceptable acid addition salt, e.g. by addition of theappropriate acid such as HCl, HI or methane-sulfonic acid to the amine.

It will be appreciated that certain products within the scope of formulaI may have substituent groups which can result in formation of opticalisomers. It is intended that the present invention include within itsscope all such optical isomers as well as epimeric mixtures thereof,i.e. R- or S- or racemic forms.

The pharmaceutically active compounds of this invention may be usedalone or formulated as pharmaceutical compositions comprising, inaddition to the active triazole ingredient, a pharmaceuticallyacceptable carrier, adjuvant or diluent. The compounds may beadministered by a variety of means, for example, orally, topically orparenterally (intravenous or intramuscular injection). Thepharmaceutical compositions may be in solid form such as capsules,tablets, powders, etc. or in liquid form such as solutions, suspensionsor emulsions. Compositions for injection may be prepared in unit doseform in ampules or in multidose containers and may contain additivessuch as suspending, stabilizing and dispersing agents. The compositionsmay be in ready-to-use form or in powder form for reconstitution at thetime of delivery with a suitable vehicle such as sterile water.

Alternatively, the compounds of the present invention can beadministered in the form of a suppository or pessary, or they may beapplied topically in the form of a lotion, solution, or cream.Additionally, they may be incorporated (at a concentration up to 10%)into an ointment consisting of a white wax or soft, white paraffin basetogether with the required stabilizers and/or preservatives.

The compounds of the invention are useful because they possesspharmacological activities in animals, including particularly mammalsand most particularly, humans. Specifically, the compounds of thepresent invention are useful for the treatment or prevention of topicalfungal infections, including those caused by species of Candida,Trichophyton, Microsporum, or Epidermophyton. Additionally, they areuseful for the treatment of mucosal infections caused by Candidaalbicans. They can also be used in the treatment of systemic fungalinfections caused, for example, by species of Candida albicans,Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus,Coccidioides, Paracoccidiodes, Histoplasma, or Blastomyces.

Thus, according to another aspect of the invention, there is provided amethod of treating a fungal infection which comprises administering atherapeutically effective amount of the compound to a host, particularlya mammalian host and most particularly a human patient. The use of thecompounds of the present invention as pharmaceuticals and the use of thecompounds of the invention in the manufacture of a medicament for thetreatment of fungal infections are also provided.

The dosage to be administered depends, to a large extent, on theparticular compound being used, the particular composition formulated,the route of administration, the nature and condition of the host andthe particular situs and organism being treated. Selection of theparticular preferred dosage and route of application, then, is left tothe discretion of the physician or veterinarian. In general, however,the compounds may be administered parenterally or orally to mammalianhosts in an amount of from about 5 mg/day to about 1.0 g/day. Thesedoses are exemplary of the average case, and there can be individualinstances where higher or lower dosages are merited, and such dosagesare within the scope of this invention. Furthermore, administration ofthe compounds of the present inventions can be conducted in eithersingle or divided doses.

The in vitro evaluation of the antifungal activities of the compounds ofthe invention can be performed by determining the minimum inhibitoryconcentration (MIC). The MIC is the concentration of test compound whichinhibits the growth of the test microorganism. In practice, a series ofagar plates, each having the test compound incorporated at a specificconcentration, is inoculated with a fungal strain and each plate is thenincubated for 48 h at 37° C. The plates are examined for the presence orabsence of fungal growth, and the relevant concentration is noted.Microorganisms which can be used in the test include Candida albicans,Asperigillus fumigatus, Trichophyton spp., Microsporum spp.,Epidermophyton floccosum, Coccidioides immitis, and Torulopsos galbrata.It should be recognized that, as prodrugs, some compounds of theinvention may not be active in the in vitro test.

The in vivo evaluation of compounds of the present invention can becarried out at a series of dose levels by intraperitoneal or intravenousinjection or by oral administration to mice which have been inoculatedwith a strain of fungus (e.g. Candida albicans). Activity is determinedby comparing the survival of the treated group of mice at differentdosage levels after the death of an untreated group of mice. The doselevel at which the test compound provides 50% protection against thelethal effect of the infection is noted.

The compounds of the present invention substantially increase thesolubility of the parent triazole antifungal compound and also releasethe bioactive parent compound (i.e. function as a prodrug) in both ratand human plasma. As shown in the table below, this is not the case withthe triazole derivatives of WO 97/28169.

Solubility Release of Parent Compound (mg/mL) in Human Plasma Parent   <0.006 — Compound of Example 1 >1 Yes Example 7 of WO 97/28169 >1 No

ILLUSTRATIVE EXAMPLES

The following examples illustrate the invention, but are not intended asa limitation thereof. The abbreviations used in the examples areconventional abbreviations well-known to those skilled in the art. Someof the abbreviations used are as follows:

h = hour(s) rt = room temperature mol = mole(s) mmol = mmole(s) g =gram(s) THF = tetrahydrofuran L = liter(s) mL = milliliter(s) Et₂O =diethyl ether EtOAc = ethyl acetate MeOH = methanol DMF =dimethylformamide DABCO = 1,4-Diazabicyclo[2.2.]octane

In the following examples, all temperatures are given in degreesCentigrade. Melting points were determined on an electrothermalapparatus and are not corrected. Proton nuclear magnetic resonance (¹HNMR) spectra were recorded on a Bruker AM-300 or a Varian Gemini 300spectrometer. All spectra were determined in CDCl₃, DMSO-d₆, CD₃OD, orD₂O unless otherwise indicated. Chemical shifts are reported in δ unitsrelative to tetramethylsilane (TMS) or a reference solvent peak andinterproton coupling constants are reported in Hertz (Hz). Splittingpatterns are designated as follows: s, singlet; d, doublet; t, triplet;q, quartet; m, multiplet; br, broad peak; dd, doublet of doublets; dt,doublet of triplets; and app d, apparent doublet, etc. Mass spectra wererecorded on a Kratos MS-50 or a Finnegan 4500 instrument utilizingdirect chemical ionization (DCI, isobutene), fast atom bombardment(FAB), or electron ion spray (ESI).

Analytical thin-layer chromatography (TLC) was carried out on precoatedsilica gel plates (60F-254) and visualized using UV light, iodinevapors, and/or staining by heating with methanolic phosphomolybdic acid.Column chromatography, also referred to as flash chromatography, wasperformed in a glass column using finely divided silica gel at pressuressomewhat above atmospheric pressure.

Preparation of (3-Chloromethyl)Benzoic Acid Chloromethyl Ester

To a cooled (0° C.) mixture of paraformaldehyde (0.79 g, 26.4 mmol) andzinc chloride (72 mg, 0.53 mmol) in benzene (10 mL) was added dropwisethe acid chloride (5.0 g, 26.4 mmol) over a period of 15 minutes. Themixture was then heated at 55° C. overnight. The mixture was thenfiltered and the filtrate concentrated. Purification of the crudeproduct via flash chromatography (100% Hexanes) yielded 2.7 g of thetitle compound as a colorless oil.

MATERIALS

3-Chloromethylbenzoyl chloride: 30 g (0.159 mole, 22.6 mL, Aldrich)

Tin (IV) Chloride: (41.35 g, 18.57 mL, 158 mole, Aldrich)

1,3,5-trioxane (14.29 g of 99% purity, 0.158 mole, Aldrich)

Dichloromethane (120 mL, EM Science, HPLC grade, KF=0.2 mG/mL)

Heptane (470 mL, EM Science, HPLC grade)

Ethylacetate (4.5 mL, EM Science, HPLC grade)

Aq. NaHCO₃ solution (saturated); 100 ml

Water (Deionised, 220 mL)

PROCEDURE

A 500 ml three neck round bottom flash equipped with a nitrogen inlet,reflux condenser, addition funnel, mechanical stirrer and immersionthermometer was charged with 60 mL CH₂Cl₂ (KF=0.2 mg/mL) and3-chloromethylbenzoylchloride. Tin (IV) chloride was added via theaddition funnel with stirring over a period of 2 minutes maintaining atemperature of 20° C.-22° C. 1,3,5-trioxane was added to the stirredmixture. The majority of the 1,3,5-trioxane remains undissolved.

The stirred suspension was kept at 20° C.-22° C. for 24 hours at the endof which the conversion was 99% (L.C. area percent). Approximately 10%of the dimer (2) was also observed by HPLC.

The reaction mixture was quenched by the addition of 120 mL water viathe addition funnel maintaining the internal temperature between 15°C.-20° C.

The reaction mixture (containing some suspended solid particles) wasfiltered through a sintered glass funnel (polish filtration) and thesolids were washed with 120 mL CH₂Cl₂. After settling, the two layersclearly separated.

The lower CH₂Cl₂ layer containing the product was separated from the topaqueous layer. The organic layer was washed with 100 mL water and thelower CH₂Cl₂ layer containing the product was separated from the topaqueous layer.

The lower CH₂Cl₂ layer containing the product was separated from the topaqueous layer. The organic layer was washed with 100 mL saturated aq.NaHCO₃ solution and the lower CH₂Cl₂ layer containing the product wasseparated from the top aqueous layer.

The lower CH₂Cl₂ layer containing the product was separated from the topaqueous layer. The CH₂Cl₂ was then replaced by heptane via distillation(under atmospheric pressure) maintaining a total volume of approximately450 mL.

1. Distillation was discontinued when the batch temperature reachedapproximately 80° C. NMR analysis of the mixture indicated completeremoval of CH₂Cl₂ at this point.

2. Approximately 470 mL heptane was used.

The mixture was cooled down to 22° C. Ethylacetate (4.5 mL) was added tothe stirred mixture and the stirred mixture was kept at 22° C. for 18 h.

1. The less soluble methanediol bis [3-chloromethyl)benzoate] (2) iscrystallized out in this process. Addition of ethylacetate helps to keepthe desired product (1) in solution.

2. When the heptane solution is cooled down to approximately 30-40° C.,some crystallization of the dimer was observed and a seed bed is formed.

3. If the dimer does not crystallize by cooling down to 22° C.,additional cooling to 0-5° C. may be necessary for the seed bed to beformed.

The crystals (dimer 2) were filtered and washed with 60 mL heptane.

1. Approximately 4.4 gm of the dimer, methanediol bis[3-chloromethyl)benzoate] was obtained.

The combined filtrate and wash containing the product was concentratedvia distillation under house vacuum to approximately 100 mL volume. Themixture was cooled to 22° C. over a period of one hour with seeding (at35° C.).

1. Crystallization begins at approximately 30° C. to 35° C.

2. Since the compound melts at 42° C., the mixture should not be seededabove 40° C.

The stirred mixture was cooled to 0-5° C. over a period of 30 minutesand then kept at 0-5° C. for 2 hours. The crystals were filtered, washedwith 20 mL of cold (10° C.) heptane, and dried in a vacuum oven at20-22° C. with a flow of nitrogen for 18 hours to yield 25.8 g (74%yield).

ANALYSES:

M.P.=41-42° C.

NMR=consistent with the structure.

HPLC

Instrument: Shimadzu LC-1OAS HPLC Detector: Shimadzu SPD M10A DiodeArray (260 nm) Column: YMC ODS AQ 4.6 × 150 mm, S-3 μm, 120A Injectionvol: 10 μL Flow Rate: 1.5 mL/min Run Time: 25 mm Eluent A: CH₃CN/water10:90 Eluent B: CH₃CN/water 90:10 Gradient Table: Time (minutes) %Eluent A % Eluent B (linear gradient)  0 60 40  5 60 40 15  0 100  20  0100  37 23 60 40 25 stop

Retention Times

3-Chloromethylbenzoyl chloride 12.28 min.

3-Chloromethylbenzoic acid (formed by hydrolysis of the acid chloride)3.46 min.

(3-Chloromethyl)benzoic acid chloromethyl ester 11.67 min.

Methanediol bis [3-chloromethyl)benzoate] (2) 14.67 min.

A.(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-(N,N-diethylaminomethyl)benzoyloxy]methoxy]butane(compound of example 28)

This two step general procedure can be employed for the preparation ofcompounds of examples 1 to 30.

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-chloromethyl)benzoyloxylmethoxy]butane

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol(1.09 mmol) was added to a suspension of potassium hydride (1.31 mmol)in THF at 0° C. The heterogeneous mixture was stirred for 0.25 hours andchloride 8 (1.14 mmol, prepared via the method of Iyer et al, Syn. Comm.25, 2739, 1995) was added. The reaction was allowed to stir at 0° C. for2 hours, and then was allowed to warm to room temperature and stirredfor 7 hours. The excess base was carefully quenched with water, and thecrude reaction was extracted into ethyl acetate. The layers wereseparated and the organic layer was washed with water, brine, and wasdried over Na₂SO₄. Purification of the crude product via columnchromatography yielded 300 mg of the subtitled compound as a colorlessoil. ¹H NMR (CDCl₃) δ8.11 (s, 1H), 7.94 (d, 2H, J=8.5), 7.88 (s, 1H),7.79 (d, 1H, J=7.8), 7.70 (m, 3H), 7.56 (d, 1H, J=7.8), 7.42 (m, 2H),7.29 (m, 1H), 6.85 (m, 2H), 6.20 (s, 2H), 5.35 (d, 2H, J=18), 5.03 (d,2H, J=18), 4.14 (m, 1H), and 1.29 (m, 3H). MS (M+=619).

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-N-N-diethylaminomethyl)benzoyloxy]methoxy]butanehydrogen chloride

N-N-diethyl amine (1.66 mmol) was added to a solution of(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-chloromethyl)benzoyloxy]methoxy]butane(0.33 mmol) in DMF (5 mL). The solution was heated to 40° C. for 3hours, was cooled to room temperature, and the DMF and excess diethylamine were removed at reduced pressure. Et₂O was added (2 mL), followedby 2 mL of a 1M solution of HCl in Et₂O, and the resulting solution wasallowed to stir at room temperature overnight. The crude reaction wasevaporated to dryness, and the resulting light yellow solid wasdissolved in H₂O (ca 30 mL) and lyophilized, resulting in 223 mg of thesubtitled compound as a yellow solid. ¹H NMR (DMSO) δ11.06 (br s, 1H),9.00 (br s, 1H), 8.66 (br s, 1H), 8.23 (s, 1H), 8.06 (m, 2H), 7.96 (m,2H), 7.87 (d, 2H, J=8), 7.82 (m, 1H), 7.47 (m, 1H), 7.37 (m, 1H), 7.22(m, 1H), 7.02 (m, 1H), 6.04 (s, 2H), 5.39 (d, 1H, J=16), 5.21 (d, 1H,J=16), 4.46 (m, 4H), 4.30 (m, 2H), 4.07 (m, 1H), and 1.21 (m, 9H). MS(M+=619).

B.(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[(4-morpholinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 31)

This three step general procedure can be employed for the preparation ofcompounds of example 31 to 43.

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol(5.8 mmol) was added to a suspension of potassium hydride (7 mmol) inTHF at 0° C. and was allowed to stir for 0.5 hours. Choromethylchloroformate (5.8 mmol, in 2 mL THF) was added dropwise and thereaction was allowed to warm to room temperature and stirred for 4hours. The crude reaction was diluted with EtOAc, and was sequentiallywashed with H₂O, 0.1N HCl, H₂O, and brine. The organic layer was driedover MgSO₄ and was concentrated to afford 3.43 g of the subtitledproduct as a pale yellow solid. ¹H NMR (DMSO) δ8.47 (s, 1H), 8.29 (s,1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8), 7.26-7.12 (m,3H), 5.93 (d, 1H, J=6), 5.90 (d, 1H, J=6), 5.70 (d, J=1H, J=15), 5.36(d, 1H, J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=530).

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[iodomethoxy]carbonyloxy]butane

NaI (19.4 mmol) was added to an acetone solution of(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane(6.5 mmol). The reaction was heated to 50° C. for 5 hours. After coolingto room temperature, the crude reaction was filtered, concentrated, andthen dissolved in EtOAc. The organic layer was washed sequentially withaqueous solutions of NaHCO₃ and Na₂S₂O₃. The organic layer was thenwashed with H₂O, dried over MgSO₄, and was concentrated to obtain 3.76 gof the subtitled compound as a yellow solid. ¹H NMR (DMSO) δ8.47 (s,1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8),7.26-7.12 (m, 3H), 6.08 (s, 2H), 5.70 (d, J=1H, J=15), 5.36 (d, 1H,J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=622).

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl-2-[[[p-[(4-morpholinyl)methyl]benzoyloxy]methoxy]carbonyloxy]butane(compound of example 31)

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[iodomethoxy]carbonyloxy]butane(1 mmol) was added to an acetonitrile solution of the carboxylate salt 9(1.6 mmol, prepared by the method of Lombardino et al, U.S. Pat. No.4,623,486) and 18-crown-6 (1.6 mmol), and the reaction was allowed tostir for 4 hours. The solution was concentrated at reduced pressure, andwas purified via column chromatography on silica. 0.48 g of thesubtitled compound was obtained as a white solid. ¹H NMR (DMSO) δ8.44(s, 1H), 8.21 (s, 1H), 7.92 (d, 2H, J=8), 7.91 (d, 2H, J=8), 7.84 (s,1H), 7.81 (d, 2H, J=8), 7.47 (d, 2H, J=8), 7.20-7.02 (m, 3H), 5.95 (d,1H, J=6), 5.93 (d, 1H, J=6), 5.66 (d, 1H, J=15), 5.35 (d, 1H, J=15),4.01 (q, 1H, J=7), 3.56 (br s, 4H), 3.53 (s, 2H), 2.34 (br s, 4H), and1.45 (d, 3H, J=7). MS (MH+=716).

We claim:
 1. The intermediate of the formula

wherein X′ is Cl, Br or I and A represents


2. The intermediate having the formula

wherein X¹ is Cl, Br or I.